Center for Human Genetics, University of Leuven, Herestraat 49, 3000, Leuven, Belgium.
Glycoconj J. 2013 Jan;30(1):67-76. doi: 10.1007/s10719-012-9445-7. Epub 2012 Sep 15.
In the past decade, the identification of most genes involved in Congenital Disorders of Glycosylation (CDG) (type I) was achieved by a combination of biochemical, cell biological and glycobiological investigations. This has been truly successful for CDG-I, because the candidate genes could be selected on the basis of the homology of the synthetic pathway of the dolichol linked oligosaccharide in human and yeast. On the contrary, only a few CDG-II defects were elucidated, be it that some of the discoveries represent wonderful breakthroughs, like e.g, the identification of the COG defects. In general, many rare genetic defects have been identified by positional cloning. However, only a few types of CDG have effectively been elucidated by linkage analysis and so-called reverse genetics. The reason is that the families were relatively small and could-except for CDG-PMM2-not be pooled for analysis. Hence, a large number of CDG cases has long remained unsolved because the search for the culprit gene was very laborious, due to the heterogeneous phenotype and the myriad of candidate defects. This has changed when homozygosity mapping came of age, because it could be applied to small (consanguineous) families. Many novel CDG genes have been discovered in this way. But the best has yet to come: what we are currently witnessing, is an explosion of novel CDG defects, thanks to exome sequencing: seven novel types were published over a period of only two years. It is expected that exome sequencing will soon become a diagnostic tool, that will continuously uncover new facets of this fascinating group of diseases.
在过去的十年中,通过生化、细胞生物学和糖生物学研究的结合,确定了大多数涉及先天性糖基化障碍 (CDG) (I 型) 的基因。这在 CDG-I 中确实非常成功,因为候选基因可以基于人类和酵母中多萜醇连接寡糖合成途径的同源性来选择。相反,只有少数 CDG-II 缺陷被阐明,尽管有些发现代表了美妙的突破,例如 COG 缺陷的鉴定。一般来说,许多罕见的遗传缺陷已经通过定位克隆被鉴定出来。然而,只有少数几种 CDG 通过连锁分析和所谓的反向遗传学得到了有效的阐明。原因是这些家族相对较小,除了 CDG-PMM2 之外,不能进行汇总分析。因此,由于搜索罪魁祸首基因非常费力,因为表型异质性和大量候选缺陷,许多 CDG 病例长期未得到解决。当纯合子作图时代到来时,这种情况发生了变化,因为它可以应用于小(近亲繁殖)家庭。通过这种方式发现了许多新的 CDG 基因。但最好的还在后头:由于外显子组测序,我们目前正在见证新的 CDG 缺陷的爆发:仅在两年的时间内就发表了七种新型 CDG。预计外显子组测序将很快成为一种诊断工具,不断揭示这组迷人疾病的新方面。